Description: The Respiratory Biology and Inhalation Toxicology (RBIT) Core has as its objective "to understand how breathing results in environmental and occupational lung disease." The core seeks to develop prevention strategies and more effective treatments for pulmonary diseases including lung cancer, asthma, pulmonary fibrosis, and emphysema. The RBIT Core is primarily concerned with the effects of inhaled environmental toxicants on the mammalian pulmonary system. The Respiratory Biology and Inhalation Toxicology Core is involved with five primary lines of investigation. First, they have investigated the mechanisms of particle binding to alveolar macrophages and epithelial cell lines. Their data suggest that the macrophage scavenger receptor system is responsible for the binding of charged particles such as latex beads and titanium dioxide as well as quartz, fly ash and urban air particulates. This system did not appear to be operative in A549 epithelial cell lines. They now wish to pursue studies of the calcium concentration dependency of this binding and inhibition of this binding by scavenger receptor ligands. They have determined that appropriately-raised polyclonal antibodies block particle binding. Thus, they would like to investigate the molecular biology of this further using scavenger receptor knock out mice and expression cloning of blocking antibodies. Lastly , they plan to study the effects of mitochondrial oxidant production on cytokine release upon exposure to quartz versus titanium. The second line of investigation seeks to elucidate the mechanism of the epidemiologic finding that mortality of cardiovascular etiology is elevated about 24 hours after peaks in the concentration of urban air particulates (PM10). To carry out these studies they have used the ambient air particle concentrator (a series of virtual impactors) built by Sioutas and Koutrakis, et al. to generate concentrated urban air aerosols from Boston ambient air. Animal models (dogs, rats, and mice) are used that attempt to recreate the susceptibility factors that are associated with mortality during urban air inversions. Included are a chronic bronchitis model, various knock out mice, and dogs with induced cardiac ischemia. The third research interest concerns the physiology and biology of airway hyper-responsiveness. This group has worked extensively with a technique that measures the stiffness of smooth muscle cell cytoskeleton by manipulating and measuring the effects of cytoskeleton-bound ferromagnetic spheres on magnetic fields. This technique allows Respiratory Biology and Inhalation Toxicology Core investigators to test the effects of cytokines or pharmacologic agents on the contractility of airway smooth muscle cells. They are also interested in developing mouse models for allergic inflammation and airway hyper-responsiveness. They describe their fourth area of research interest as the development and application of bioassays for lung injury. For the most part this appears to be an effort to bring published assays into the laboratory s repertoire. Assays include lavage cytokines, enzymes, proteins, and message for several mediators. The last area of investigation described for the Respiratory Biology and Inhalation Toxicology Core is studies of the molecular mechanisms of pulmonary inflammation. In this work the investigators are considering signal transduction pathways for lung cell adhesion and the dynamics of neutrophil migration into the lung. They are also investigating the cells and chemokines that trigger the release of reactive oxygen species. In particular, they have studied rat MIP-1 alpha and MIP-2, a neutrophil chemotactic chemokine. Within these research studies is evidence of collaboration between the Respiratory Biology and Inhalation Toxicology Core and several other cores and facilities within the Center. Most notable are the Environmental Epidemiology Research Core and the Toxicology Research Core although there is reference to the Occupational Health Core and the Environmental Sciences and Engineering Core as well. The Respiratory Biology and Inhalation Toxicology Core investigators rely on a number of facilities for equipment and expertise. A central molecular biology laboratory provides nucleic acid and protein sequencing, PCR, in site hybridization and immunocytochemistry. Tissue and cell culture facilities are maintained within the Physiology Program. The Bioimaging Core provides laser scanning, confocal microscopy and morphometrics capabilities. The two electron microscopy laboratories offer scanning and transmission electron microscopy with electron specrtoscope imaging capabilities. An inhalation toxicology laboratory has three 1m3 Lucite chambers and two 100 l Lucite chambers. They are primarily set-up for the generation of gases (ozone and So2) and for concentrated Boston ambient air particles. The Respiratory Biology and Inhalation Toxicology Core is equipped with devices for blood and gaseous phase gas analysis and devices for respiratory mechanics and electrophysiology. Lastly, the core has developed a device for magnetometry in order to study changes in cytoskeletal stiffness.